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Molecular determinants of voltage-dependent human ether-a-go-go related gene (HERG) K+ channel block.
J Biol Chem. 2002 Jun 28; 277(26):23587-95.JB

Abstract

The structural determinants for the voltage-dependent block of ion channels are poorly understood. Here we investigate the voltage-dependent block of wild-type and mutant human ether-a-go-go related gene (HERG) K(+) channels by the antimalarial compound chloroquine. The block of wild-type HERG channels expressed in Xenopus oocytes was enhanced as the membrane potential was progressively depolarized. The IC(50) was 8.4 +/- 0.9 microm when assessed during 4-s voltage clamp pulses to 0 mV. Chloroquine also slowed the apparent rate of HERG deactivation, reflecting the inability of drug-bound channels to close. Mutation to alanine of aromatic residues (Tyr-652 or Phe-656) located in the S6 domain of HERG greatly reduced the potency of channel block by chloroquine (IC(50) > 1 mm at 0 mV). However, mutation of Tyr-652 also altered the voltage dependence of the block. In contrast to wild-type HERG, block of Y652A HERG channels was diminished by progressive membrane depolarization, and complete relief from block was observed at +40 mV. HERG channel block was voltage-independent when the hydroxyl group of Tyr-652 was removed by mutating the residue to Phe. Together these findings indicate a critical role for Tyr-652 in voltage-dependent block of HERG channels. Molecular modeling was used to define energy-minimized dockings of chloroquine to the central cavity of HERG. Our experimental findings and modeling suggest that chloroquine preferentially blocks open HERG channels by cation-pi and pi-stacking interactions with Tyr-652 and Phe-656 of multiple subunits.

Authors+Show Affiliations

Unidad de Investigación Carlos Méndez del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, 23000 Colima, México.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

11960982

Citation

Sánchez-Chapula, Jose A., et al. "Molecular Determinants of Voltage-dependent Human Ether-a-go-go Related Gene (HERG) K+ Channel Block." The Journal of Biological Chemistry, vol. 277, no. 26, 2002, pp. 23587-95.
Sánchez-Chapula JA, Navarro-Polanco RA, Culberson C, et al. Molecular determinants of voltage-dependent human ether-a-go-go related gene (HERG) K+ channel block. J Biol Chem. 2002;277(26):23587-95.
Sánchez-Chapula, J. A., Navarro-Polanco, R. A., Culberson, C., Chen, J., & Sanguinetti, M. C. (2002). Molecular determinants of voltage-dependent human ether-a-go-go related gene (HERG) K+ channel block. The Journal of Biological Chemistry, 277(26), 23587-95.
Sánchez-Chapula JA, et al. Molecular Determinants of Voltage-dependent Human Ether-a-go-go Related Gene (HERG) K+ Channel Block. J Biol Chem. 2002 Jun 28;277(26):23587-95. PubMed PMID: 11960982.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Molecular determinants of voltage-dependent human ether-a-go-go related gene (HERG) K+ channel block. AU - Sánchez-Chapula,Jose A, AU - Navarro-Polanco,Ricardo A, AU - Culberson,Chris, AU - Chen,Jun, AU - Sanguinetti,Michael C, Y1 - 2002/04/17/ PY - 2002/4/19/pubmed PY - 2002/8/7/medline PY - 2002/4/19/entrez SP - 23587 EP - 95 JF - The Journal of biological chemistry JO - J Biol Chem VL - 277 IS - 26 N2 - The structural determinants for the voltage-dependent block of ion channels are poorly understood. Here we investigate the voltage-dependent block of wild-type and mutant human ether-a-go-go related gene (HERG) K(+) channels by the antimalarial compound chloroquine. The block of wild-type HERG channels expressed in Xenopus oocytes was enhanced as the membrane potential was progressively depolarized. The IC(50) was 8.4 +/- 0.9 microm when assessed during 4-s voltage clamp pulses to 0 mV. Chloroquine also slowed the apparent rate of HERG deactivation, reflecting the inability of drug-bound channels to close. Mutation to alanine of aromatic residues (Tyr-652 or Phe-656) located in the S6 domain of HERG greatly reduced the potency of channel block by chloroquine (IC(50) > 1 mm at 0 mV). However, mutation of Tyr-652 also altered the voltage dependence of the block. In contrast to wild-type HERG, block of Y652A HERG channels was diminished by progressive membrane depolarization, and complete relief from block was observed at +40 mV. HERG channel block was voltage-independent when the hydroxyl group of Tyr-652 was removed by mutating the residue to Phe. Together these findings indicate a critical role for Tyr-652 in voltage-dependent block of HERG channels. Molecular modeling was used to define energy-minimized dockings of chloroquine to the central cavity of HERG. Our experimental findings and modeling suggest that chloroquine preferentially blocks open HERG channels by cation-pi and pi-stacking interactions with Tyr-652 and Phe-656 of multiple subunits. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/11960982/Molecular_determinants_of_voltage_dependent_human_ether_a_go_go_related_gene__HERG__K+_channel_block_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=11960982 DB - PRIME DP - Unbound Medicine ER -